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Journal of the American Heart... Jun 2024Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins...
Monoclonal Antibody chP3R99 Reduces Subendothelial Retention of Atherogenic Lipoproteins in Insulin-Resistant Rats: Acute Treatment Versus Long-Term Protection as an Idiotypic Vaccine for Atherosclerosis.
BACKGROUND
Atherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to low-density lipoprotein, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported antiatherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans.
METHODS AND RESULTS
Solid-phase assays demonstrated that chP3R99 effectively blocked >50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The preperfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by ~60% in insulin resistant JCR:LA- rats. This competitive reduction was dose dependent (25-250 μg/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a 5-week vaccination study in insulin resistant rats with (200 μg subcutaneously, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of antichondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA rats.
CONCLUSIONS
Both acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced low-density lipoprotein and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting proatherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis.
PubMed: 38934863
DOI: 10.1161/JAHA.123.032419 -
Indian Journal of Public Health Oct 2023In children, body frame size estimation is used to interpret body mass and evaluate growth patterns. The present study aims to assess the body frame size by elbow...
In children, body frame size estimation is used to interpret body mass and evaluate growth patterns. The present study aims to assess the body frame size by elbow breadth and frame index and its relation to body composition parameters among tribal preschool children (1-5 years of age). In the present study, 848 preschool children (430 boys and 418 girls) were included. The mean elbow breadth showed an increasing trend with increasing age, but inverse results were observed in the case of frame index. Age-wise, statistically significant sex differences were found in mean elbow breadth and frame index (except for 2 years of age). Boys show higher mean elbow breadth and frame index in all age groups, and significant sex differences were found. Elbow breadth and frame index had the strongest significant positive correlations with fat free mass (FFM) (r = 0.590, P < 0.01) and FFM index (r = 0.539, P < 0.01), respectively.
Topics: Humans; Child, Preschool; India; Male; Female; Body Composition; Infant; Elbow; Anthropometry; Sex Factors; Age Factors; Body Size
PubMed: 38934810
DOI: 10.4103/ijph.ijph_1497_22 -
Indian Journal of Dental Research :... Jan 2024Periodontitis and type 2 diabetes are chronic inflammatory diseases that increase inflammatory Interleukin-6 (IL-6) levels that induce the production of advanced...
BACKGROUND
Periodontitis and type 2 diabetes are chronic inflammatory diseases that increase inflammatory Interleukin-6 (IL-6) levels that induce the production of advanced glycation end products (AGEs) causing receptor activator of nuclear factor-kappa B ligand (RANKL) expression on osteoclasts, contributing to further alveolar bone destruction.
AIM
To assess the role and diagnostic potential of salivary IL-6 (SIL-6) in the detection and evaluation of chronic periodontitis (CP) and tooth loss in type 2 diabetes mellitus (T2DM).
MATERIALS AND METHODS
This cross-sectional study comprised 240 subjects aged 30-69 years with minimum of 15 natural teeth. Fasting, unstimulated whole saliva was collected, full-mouth intra-oral examination and periodontal evaluation were performed using PCP-UNC 15 probe and glycaemic (HbA1c) levels were analysed by high-performance liquid chromatography (HPLC) method. Subjects were categorised into four groups of 60 participants each: Group 1 (controls); Group 2 (CP); Group 3 (T2DM with CP); Group 4 (T2DM with CP and tooth loss). Salivary IL-6 levels were quantitatively assessed by enzyme-linked immune sorbent assay method.
RESULTS
Average SIL-6 levels were significantly elevated in Group 4 (T2DM with CP and tooth loss) (P = 0.001) and in severe periodontitis (P = 0.001). Karl Pearson Correlation found a significant association between average SIL-6 and average periodontal pocket depth (APPD) (r = 0.180), average clinical attachment loss ≥3 mm (ACAL3) (r = 0.289) and severity of periodontitis (r = 0.3228). The receiver operating characteristic (ROC) curve depicted an overall sensitivity of 53.3%, specificity of 68.6% and accuracy of 60% in the detection and assessment of CP in T2DM with tooth loss.
CONCLUSION
IL-6 in saliva is a valuable, non-invasive biomarker in the detection and evaluation of CP in T2DM with tooth loss.
Topics: Humans; Chronic Periodontitis; Middle Aged; Interleukin-6; Saliva; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Tooth Loss; Adult; Male; Aged
PubMed: 38934745
DOI: 10.4103/ijdr.ijdr_112_23 -
Hepatology Communications Jul 2024MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its...
BACKGROUND
MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear.
METHODS
Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH.
RESULTS
We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis.
CONCLUSIONS
These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.
Topics: Animals; Mice; Hepatocytes; Liver Cirrhosis; Mice, Knockout; DNA-Binding Proteins; Humans; HMGB1 Protein; Fatty Liver; Male; Choline Deficiency; Disease Models, Animal; Methionine; Liver; Lipid Metabolism
PubMed: 38934719
DOI: 10.1097/HC9.0000000000000474 -
Hepatology Communications Jul 2024The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown.
BACKGROUND
The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown.
METHODS
Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF).
RESULTS
Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF.
CONCLUSIONS
We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.
Topics: Animals; Myosin-Light-Chain Phosphatase; Mice; Disease Models, Animal; Liver Cirrhosis; Cholestasis; Gallbladder Diseases; Gallbladder; Male; Mice, Knockout
PubMed: 38934703
DOI: 10.1097/HC9.0000000000000473 -
Annals of Human Biology Feb 2024Rising global obesity rates are linked with inflammation and associated morbidities. These negative outcomes are generally more common in low-resource communities within...
BACKGROUND
Rising global obesity rates are linked with inflammation and associated morbidities. These negative outcomes are generally more common in low-resource communities within high-income countries; however, it is unclear how frequent infectious disease exposures in these settings may influence the relationship between adiposity and inflammation.
AIM
We test associations between adiposity measures and distinct forms of inflammation among adults ( = 80) living in low-resource U.S. communities experiencing high levels of obesity and pathogen exposure.
SUBJECTS AND METHODS
Adiposity measures included BMI and percent body fat. Inflammation measures included systemic inflammation (C-reactive protein [CRP]) and localised intestinal inflammation (faecal calprotectin [FC]). The relationship between a condition characterised by elevated inflammation ( infection) and adiposity was also considered.
RESULTS
Adiposity was not significantly related to FC concentration. However, both adiposity measures were positively related with odds of CRP elevation and infection was associated with significantly lower adiposity measures (all < 0.05).
CONCLUSION
For this disadvantaged U.S. sample, the association between adiposity and inflammation varies by the systemic/localised nature of inflammation and the likely underlying cause of inflammation. Defining these associations will improve understanding of how rising obesity rates shape long-term health inequities, with implications for more effective intervention design.
Topics: Humans; Adiposity; Inflammation; Female; Male; Adult; Middle Aged; Chronic Disease; United States; C-Reactive Protein; Helicobacter Infections; Helicobacter pylori; Leukocyte L1 Antigen Complex; Obesity; Young Adult; Body Mass Index; Aged; Feces
PubMed: 38934696
DOI: 10.1080/03014460.2024.2368851 -
MSphere Jun 2024Bacterial ribonuclease E (RNase E) is vital for posttranscriptional regulation by degrading and processing RNA. The RraA protein inhibits RNase E activity through...
Bacterial ribonuclease E (RNase E) is vital for posttranscriptional regulation by degrading and processing RNA. The RraA protein inhibits RNase E activity through protein-protein interactions, exerting a global regulatory effect on gene expression. However, the specific role of RraA remains unclear. In this study, we investigated expression in ZJ-T and identified three promoters responsible for its expression, resulting in transcripts with varying 5'-UTR lengths. During the stationary phase, was significantly posttranscriptionally inhibited. Deletion of had no impact on bacterial growth in rich medium Luria-Bertani broth with salt (LBS) but resulted in decreased biofilm formation and increased resistance to polymyxin B. Transcriptome analysis revealed 350 differentially expressed genes (DEGs) between the wild type and the mutant, while proteome analysis identified 267 differentially expressed proteins (DEPs). Integrative analysis identified 55 genes common to both DEGs and DEPs, suggesting that RraA primarily affects gene expression at the posttranscriptional level. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis demonstrated that RraA facilitates the conversion of fatty acids, propionic acid, and branched-chain amino acids to acetyl-CoA while enhancing amino acid and peptide uptake. Notably, RraA positively regulates the expression of virulence-associated genes, including those involved in biofilm formation and the type VI secretion system. This study expands the understanding of the regulatory network of RraA through transcriptome analysis, emphasizing the importance of proteomic analysis in investigating posttranscriptional regulation.IMPORTANCERraA is an inhibitor protein of ribonuclease E that interacts with and suppresses its endonucleolytic activity, thereby playing a widespread regulatory role in the degradation and maturation of diverse mRNAs and noncoding small RNAs. However, the physiological functions and associated regulon of RraA in have not been fully elucidated. Here, we report that RraA impacts virulence-associated physiological processes, namely, antibiotic resistance and biofilm formation, in . By conducting an integrative analysis of both the transcriptome and proteome, we revealed the involvement of RraA in carbon metabolism, amino acid catabolism, and transport, as well as in the type VI secretion system. Collectively, these findings elucidate the regulatory influence of RraA on multiple pathways associated with metabolism and pathogenesis in .
PubMed: 38934599
DOI: 10.1128/msphere.00020-24 -
MSystems Jun 2024is the dominant species of the genus in the gut, which is genomically heterogeneous and difficult to isolate; hence, scarce research was carried out for this species....
UNLABELLED
is the dominant species of the genus in the gut, which is genomically heterogeneous and difficult to isolate; hence, scarce research was carried out for this species. This study aimed to investigate the effect of on hyperglycemia. Thirty-nine strains were isolated from healthy individuals, and three strains (HF2123, HF1478, and HF2130) that had the highest glucose consumption were selected to evaluate the effects of supplementation on hyperglycemia. Microbiomics and non-target metabolomics were used to uncover the underlying mechanisms. Oral administration of in diabetic db/db mice increased the expression and secretion of glucagon-like peptide-1 (GLP-1), significantly improved hyperglycemia, insulin resistance, and lipid accumulation, and alleviated the pathological morphology in the pancreas, liver, and colon. changed the composition of the gut microbiota of diabetic db/db mice, which was characterized by increasing the ratio of Bacteroidetes to Firmicutes and increasing the relative abundance of genera , , and . After intervention with , fecal metabolic profiling showed that fumaric acid and homocysteine contents decreased, and glutamine contents increased. Furthermore, amino acid metabolism and cAMP/PKA signaling pathways were enriched. Our findings indicate that improved glucose metabolism abnormalities in diabetic db/db mice. Especially, one of the strains, HF2130, has shown superior performance in improving hyperglycemia, which may have the potential as a probiotic against hyperglycemia.
IMPORTANCE
As a core member of the human intestinal ecosystem, has been associated with glucose metabolic homeostasis in previous studies. However, these results have often been derived from metagenomic studies, and the experimental studies have been based solely on the type of strain DSM 18205. Therefore, more experimental evidence from additional isolates is needed to validate the results according to their high genomic heterogeneity. In this study, we isolated different branches of strains and demonstrated that could improve the metabolic profile of hyperglycemic mice by modulating microbial activity. This finding supports the causal contribution of in host glucose metabolism.
PubMed: 38934548
DOI: 10.1128/msystems.00532-24 -
MSystems Jun 2024is a Gram-negative commensal bacterium commonly found in the human colon, which differentiates into two genomospecies termed divisions I and II. Through a comprehensive...
UNLABELLED
is a Gram-negative commensal bacterium commonly found in the human colon, which differentiates into two genomospecies termed divisions I and II. Through a comprehensive collection of 694 whole genome sequences, we identify novel features distinguishing these divisions. Our study reveals a distinct geographic distribution with division I strains predominantly found in North America and division II strains in Asia. Additionally, division II strains are more frequently associated with bloodstream infections, suggesting a distinct pathogenic potential. We report differences between the two divisions in gene abundance related to metabolism, virulence, stress response, and colonization strategies. Notably, division II strains harbor more antimicrobial resistance (AMR) genes than division I strains. These findings offer new insights into the functional roles of division I and II strains, indicating specialized niches within the intestine and potential pathogenic roles in extraintestinal sites.
IMPORTANCE
Understanding the distinct functions of microbial species in the gut microbiome is crucial for deciphering their impact on human health. Classifying division II strains as can lead to erroneous associations, as researchers may mistakenly attribute characteristics observed in division II strains to the more extensively studied division I . Our findings underscore the necessity of recognizing these divisions as separate species with distinct functions. We unveil new findings of differential gene prevalence between division I and II strains in genes associated with intestinal colonization and survival strategies, potentially influencing their role as gut commensals and their pathogenicity in extraintestinal sites. Despite the significant niche overlap and colonization patterns between these groups, our study highlights the complex dynamics that govern strain distribution and behavior, emphasizing the need for a nuanced understanding of these microorganisms.
PubMed: 38934546
DOI: 10.1128/msystems.00516-24 -
Microbial Biotechnology Jun 2024Bdellovibrio bacteriovorus HD100 is an obligate predatory bacterium that preys upon Gram-negative bacteria. It has been proposed to be applied as a "living antibiotic"...
Bdellovibrio bacteriovorus HD100 is an obligate predatory bacterium that preys upon Gram-negative bacteria. It has been proposed to be applied as a "living antibiotic" in several fields such as agriculture or even medicine, since it is able to prey upon bacterial pathogens. Its interesting lifestyle makes this bacterium very attractive as a microbial chassis for co-culture systems including two partners. A limitation to this goal is the scarcity of suitable synthetic biology tools for predator domestication. To fill this gap, we have firstly adapted the hierarchical assembly cloning technique Golden Standard (GS) to make it compatible with B. bacteriovorus HD100. The chromosomal integration of the Tn7 transposon's mobile element, in conjunction with the application of the GS technique, has allowed the systematic characterization of a repertoire of constitutive and inducible promoters, facilitating the control of the expression of heterologous genes in this bacterium. PJ/EliR proved to be an exceptional promoter/regulator system in B. bacteriovorus HD100 when precise regulation is essential, while the synthetic promoter P showed a constitutive high expression. These genetic tools represent a step forward in the conversion of B. bacteriovorus into an amenable strain for microbial biotechnology approaches.
Topics: Synthetic Biology; Bdellovibrio bacteriovorus; Gene Expression Regulation, Bacterial; Promoter Regions, Genetic; DNA Transposable Elements; Cloning, Molecular; Recombinant Proteins
PubMed: 38934530
DOI: 10.1111/1751-7915.14517